Prodrug Strategies for HCV Nucleoside Lead Development

描述（由申请人提供）：全球估计有超过2亿人慢性感染丙型肝炎病毒，并因此面临发展危及生命的肝脏疾病的风险。目前唯一可用的治疗方法是聚乙二醇化干扰素和核苷类似物利巴韦林的联合治疗。不幸的是，这种组合在不到一半的治疗患者中显示出有限的疗效，并且受到治疗限制的副作用和毒性的困扰。此外，越来越多的临床试验小分子耐药报告正在出现，强调需要新的和更有效的治疗方法。许多修饰的核苷已显示出作为HCV聚合酶抑制剂的有效活性，然而，由于递送无效、毒性、不稳定性和/或药代动力学差等问题，使得许多有希望的类似物不适合，因此许多研究人员转向在核苷的5'-OH上使用前药或“掩膜”基团来克服这些问题。该应用侧重于一系列扩展的嘌呤核苷类似物，我们预计由于一些战略性设计的结构特征，这些类似物将对HCV RNA依赖性RNA聚合酶（RdRp） NS5B表现出有效的活性。这个应用程序的影响是双重的；首先，由于迫切需要更有效的丙型肝炎治疗方法，这些医学发现最终可能会产生全球影响。此外，基本的科学影响包括扩大我们对特定靶向HCV NS5B聚合酶和肝细胞的药物递送方法的知识广度。此外，新的和改进的核苷类似物的合成方法将进行研究。因此，这项工作的科学影响不仅限于全球卫生研究，而且还将为学生提供宝贵的培训，因为合成有机和药物输送方法以及所获得的有关聚合酶的信息将高度适用于广泛的疾病。

DESCRIPTION (provided by applicant): More than 200 million people worldwide are estimated to be chronically infected with HCV and as a result, at risk for developing life-threatening liver diseases. The only treatment currently available is a combination therapy of pegylated interferon and Ribavirin, a nucleoside analogue. Unfortunately this combination has exhibited limited efficacy in less than half of treated patients, as well as being plagued with treatment- limiting side effects and toxicity. In addition, increasing reports of drug resistance to investigational small molecules in clinical trials are emerging, underscoring the need for new and more effective treatments. A number of modified nucleosides have exhibited potent activity as inhibitors of HCV polymerase, however problems with ineffective delivery, toxicity, instability and/or poor pharmacokinetics have rendered many promising analogues unsuitable, thus many researchers are turning to use of a prodrug, or "masking" group, on the 5'-OH of the nucleoside, to overcome these problems. This application focuses on a series of expanded purine nucleoside analogues that we anticipate will exhibit potent activity against the HCV RNA-dependent RNA polymerase (RdRp) NS5B due to a number of strategically designed structural features. The impact of this application is two-fold; one, the medicinal discoveries could ultimately have a global impact, as more effective HCV treatments are desperately needed. In addition, the basic scientific impacts include expanding the breadth of our knowledge of drug delivery methods for specific targeting of the HCV NS5B polymerase, as well as liver cells. In addition, new and improved methodology for nucleoside analogue synthesis will be investigated. As such, the scientific impact of this work goes beyond just global health research, but will also provide valuable training for students, as the synthetic organic and drug delivery methodologies and the information obtained about polymerases will be highly applicable across a broad scope of diseases.